title: Smad2 and Smad3 cooperate and antagonize simultaneously in vertebrate neurogenesis.
abstract: The transforming growth factor beta (TGF-β) pathway plays key roles in development and cancer. TGF-β signaling converges on the Smad2 and Smad3 effectors, which can either cooperate or antagonize to regulate their transcriptional targets. Here we performed in vivo and in silico experiments to study how such cooperativity and antagonism might function during neurogenesis. In vivo electroporation experiments in the chick embryo neural tube show that Smad2 and Smad3 cooperate to promote neurogenesis, as well as the transcription of Smad3-specific targets. Knockdown of Smad2 enhances neurogenesis and the transcription of Smad3-specific targets. A mathematical model of the TGF-β pathway fits the experimental results and predicts that the proportions of the three different trimeric complexes formed dictates the transcriptional responses of the R-Smad proteins. As such, Smad2 targets are activated solely by the Smad2-Smad2-Smad4 complex, whereas Smad3 targets are activated both by Smad2-Smad3-Smad4 and Smad3-Smad3-Smad4 trimers. We have modeled the Smad responses onto arbitrary genes and propose that this mechanism might be extended to additional activities of TGF-β in development and disease.
authors.affiliation: Instituto de Biología Molecular de Barcelona, CSIC, C/Baldiri i Reixac 20, Barcelona 08028, Spain.
authors.forename: David G
authors.initials: DG
authors.lastname: Míguez
authors.forename: Estel
authors.initials: E
authors.lastname: Gil-Guiñón
authors.forename: Sebastián
authors.initials: S
authors.lastname: Pons
authors.forename: Elisa
authors.initials: E
authors.lastname: Martí
mesh_terms: D000818:Animals; D002642:Chick Embryo; D003198:Computer Simulation; D018274:Electroporation; D018507:Gene Expression Regulation, Developmental; D008957:Models, Genetic; D055495:Neurogenesis / Q000235:genetics*; D055503:Protein Multimerization; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D051899:Smad2 Protein / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D051900:Smad3 Protein / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D051901:Smad4 Protein / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D014158:Transcription, Genetic; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism
chemical_list: D034741:RNA, Small Interfering; D051899:Smad2 Protein; D051900:Smad3 Protein; D051901:Smad4 Protein; D016212:Transforming Growth Factor beta
keywords: Chick embryo; Differential equations; Neural tube; Neurogenesis